The present invention relates to N-hydroxy- and N-amino-quinazolinones and methods for preparing such compounds.
There is a great interest in synthetic methods directed toward the creation of large collections of small organic compounds, or libraries, which could be screened for pharmacological, biological or other activity. Often referred to as combinatorial chemistry, the synthetic methods applied to create vast combinatorial libraries are performed in solution or in the solid phase, i.e., on a solid support. Further, solid-phase synthesis makes it easier to conduct multi-step reactions and to drive reactions to completion with high yields because excess reagents can be easily added and washed away after each reaction step. Solid-phase combinatorial synthesis also tends to improve isolation, purification and screening. However, the more traditional solution phase chemistry supports a wider variety of organic reactions than solid-phase chemistry.
Typically, combinatorial methods involve the addition of various structural components sequentially, either in a controlled or random manner to a core chemical structure in order to produce all or a substantial portion of the possible combinations that can result from the different possible reactions at each stage. The efficient use of this technique can create thousands of compounds for pharmacological screening in a rapid fashion.
Methods for screening libraries of compounds for binding properties to a receptor include methods wherein each member of the library is tagged with a unique identifier to facilitate identification of compounds having binding properties, or where the library comprises a plurality of compounds synthesized at particular locations on the surface of a solid substrate. The receptor may be appropriately labelled with a radioactive or fluorescent label that enables one to ascertain whether binding to the receptor of interest has occurred. Correlation of the labelled receptor bound to the substrate, which has its location on the substrate, identifies the binding ligand as disclosed in U.S. Pat. No. 5,143,854.
In contrast to the standard combinatorial chemistry approach which results in libraries with maximum diversity, there is a trend toward the design of more targeted libraries, particularly of small compounds, which minimize redundancy and improve screening efficiency.
One particular class of compounds that would be useful for inclusion in targeted libraries is quinazolinone compounds such as N-hydroxy-quinazolinones and derivatives thereof. Quinazolinone compounds possess a diverse array of beneficial pharmaceutical and chemical properties. For example, certain quinazolinones are known to possess antipyretic, hypotensive, antibacterial, antifungal or central nervous system (CNS) activity, as well as the ability to inhibit enzymes of biological importance, such as metalloenzymes.
C. Schapira and S. Lamdan (J. Heterocyclic Chem., 9:569-576 (1972)) disclose the action of various simple acylating agents on 2-aminobenzohydroxamic acid, which afforded 3-hydroxy-4(3H)-quinazolinones (hydroxamic acids), as well as several ethers and esters derived therefrom.
H. Kohl and E. Wolf (Liebigs Ann. Chem., 766:106-115 (1972)) disclose that O-alkyl N-acylaminobenzhydroxamates are readily cyclized to 2-substituted-3-alkoxyquinazolinones.
M. Ghelardoni and v. Pestellini (Annali di Chimica, 64:445-453 (1974)) disclose the synthesis of fused-ring systems containing the 4-quinazolone nucleus. These compounds are obtained by condensation of o-aminobenzoylhydrazine or o-aminobenzohydroxamic acid with compounds containing both carbonyl and carboxyl groups, such as phthalaldehydic acid or levulinic acid, or with cyclic anhydrides, such as phthalic anhydride or succinic anhydride.
K. Tanaka et al. (Chem. Pharm. Bull., 36(7):2323-2330 (1988)) disclose the synthesis of 3-Hydroxy-4-oxo-3,4 dihydroquinazolinones, which exhibited metal chelating abilities, analgesic-activities, and inhibition of the growth of microorganisms. The 3-hydroxy-4-oxo-3,4-dihydroquinazolinones were prepared, for example, by reacting a 2-aminobenzohydroxamic acid with acetic anhydride or formic acid.
Although, a variety of syntheses of quinazolinones using solution-phase techniques have been reported, there is a need for a general method of synthesis of such compounds, especially in the solid phase. In other words, there is a need for a solid-phase synthesis that allows one to synthesize a multiplicity of quinazolinones on a variety of sold supports, as well as a need for preparing and screening a library of quinazolinones for pharmacological or biological activities.
Accordingly, there is a need in the art for an efficient method for obtaining a library of N-hydroxy- and N-amino quinazolinones, particularly 3-hydroxy-quinazolinones and 3-amino-quinazolinones, wherein the starting materials are amenable to large scale synthesis.
Citation or identification of any reference in this section of this application shall not be construed as an admission that such reference is available as prior art to the application.
The present invention is directed to synthesis of N-amino and N-hydroxy-quinazolinone compounds on solid supports. The use of solid support in the present invention both allows for protection of the N-moiety and facilitates purification and/or isolation. The synthesis of the instant invention is particularly useful since mild conditions are involved.
In general terms, the invention involves the coupling of a substituted or unsubstituted isatoic anhydride to a solid support, preferably a solid support containing a hydrazino or hydroxylamine moiety that is available for reaction. This coupling reaction forms a 2-aminobenzamide which is bound to the solid support via the amide-nitrogen, thereby both protecting and anchoring the 2-aminobenzamide. The bound 2-aminobenzamide is subsequently reacted with a compound of the formula
R2xe2x80x94CHYxe2x80x94COxe2x80x94X or Wxe2x80x94COxe2x80x94X 
wherein X is OH, Cl, F, Br or a carboxylic acid activating group; Y is NR3R4 where NR3R4 is an N-protected-amino acid, or Cl, Br, or F and R2 is a substituted or unsubstituted alkyl, aryl, alkylaryl group and W is a heterocyclic group to form a cyclized compound, i.e., a quinazolinone. It should be recognized that a variety of quinazolinone can be prepared depending upon the compound chosen for coupling. Further, the resulting solid-phase bound product can either be further modified or simply cleaved, or both. Thus, a vast number of quinazolinone compounds can be prepared and screened for potential biological activity.
The present invention is directed, in one of its aspects, to general synthetic methods for incorporating a N-amino or N-hydroxy-4(1H)-quinazolinone of the formula (I) onto a solid support. 
wherein R1 is an independently selected mono-, di-, tri-, or quad-substitution on the phenyl ring, and where R1 is independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl optionally substituted with halogen, hydroxy, C1-C6 alkoxy and aryl, or hydroxy, C1-C6 alkoxy, NO2, SO2Ph, phenyl SO2NR3R4, OCOR5, SR5, CO2R5; NHCOR5; or R1, when disubstituted, can be taken together to form a 5, 6 or 7-membered carbocyclic aromatic group or heterocyclic aromatic group wherein the heterocyclic aromatic group is selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or indolyl;
R2 is branched or straight chain C1-C6 alkyl, C1-C6 alkoxy, a nitrogen-protected amino acid, phenyl, benzyl, C1-C6 alkenyl, hydroxy, SO2Ph, SO2NR3R4, NR3R4, OCOR5, SR5, CO2R5, NHCOR5, or a heterocyclic aromatic group, whereby R2 is unsubstituted or substituted;
R3 and R4 are independently hydrogen, C1-C6 alkyl or, taken together are (CH2)f where f is 3-6;
R5 is C1-C6 alkyl, benzyl, phenyl, or, substituted phenyl with 1-3 substituents independently selected from the group consisting of C1-C6 alkoxy, NO2, CF3, or CN; and
Y is an appropriate cleavable linker such as xe2x80x94NHCO2CH2xe2x80x94 or xe2x80x94Oxe2x80x94CH2, linked to a suitable solid support.
These compounds may possess antipyretic, hypotensive, antibacterial, antifungal or CNS activity, or the ability to inhibit enzymes of biological importance, such as metalloenzymes. The compounds may be any 3-hydroxy-4(1H)-quinazolinone, as described herein.
Preferred compounds are where R1 is an independently selected mono-, di-, tri-, or quad-substitution on the phenyl ring, of a branched or straight C1-C10 alkyl, C4-C10 aryl, fluorine, chlorine, bromine, iodine, NO2, C1-C10 alkoxy, C1-C1, alkenyl, C1-C10 aralkyl, C1-C10 aralkenyl, hydroxy, SO2Ph, SO2NR3R4NR3R4, OCOR5, SR5, CO2R5, or NHCOR5; and R2 is a branched or straight C1-C10 alkyl, C4-C10 aryl, C1-C10 alkoxy, C4-C10 aryloxy, NHCO2R5, C1-C10 alkenyl, hydroxy, SO2Ph, SO2NR3R4, NR3R5, OCOR5, SR5, CO2R5, NHCOR5, or a 4-10 membered heterocyclic group; wherein R3 and R4 are independently hydrogen, a branched or straight C1-C10 alkyl, C4-C10 aryl, a halogen, C1-C10 alkoxy, C4-C10 aryloxy, C1-C10 alkenyl, C1-C10 aralkyl, C1-C10 aralkenyl, hydroxy, SO2Ph, or NH2.
More preferred compounds are those where R1 is C1-C8 alkyl, C5-C7 aryl, fluorine, chlorine, bromine, iodine, or NO2; and R2 is C1-C8 alkyl, C5-C7 aryl, NHCO2R5, or a 5-7 membered heterocyclic aromatic compound selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or indolyl.
Solid supports containing the N-amino- or N-hydroxy-4 (1H)-quinazolinone group comprise a cleavable linker or linking arm which links the solid support to the compound. The linking arm is typically an oxygen-containing moiety that is cleavable by treatment with an organic or inorganic acid, thereby yielding the free N-amino-or N-hydroxy-4(1H)-quinazolinone. The library of compounds that can be generated on the solid support comprises a diverse array of substituted N-amino or N-hydroxy-4(1H)-quinazolinones, that once cleaved, can be screened to identify and/or isolate individual compounds that bind to a specific protein or receptor or possess some desired pharmacological or chemical property.